Cytotoxic T Cells Early after Lung Transplantation Precede the Restrictive Allograft Syndrome

Abstract

Purpose The outcome after lung transplantation is limited by chronic lung allograft dysfunction (CLAD), subclassified into bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). RAS tends to an earlier, more severe and more rapid course as compared to BOS. Underlying differences of the immunologic phenotype, potentially unveiling therapeutic targets, have not yet been well-defined. Methods From June 2013 to August 2015, we collected whole blood samples from 142 consecutively transplanted patients 3 weeks after lung transplantation, excluding only those patients with missing blood samples or who did not consent to have the samples drawn. The samples were analyzed by flow cytometry. CD3+ CD8+ T cells were defined as cytotoxic T cells. Follow up ended as of 09/2018 and full data was available from 138 patients. CLAD diagnosis was made according to ISHLT consensus criteria based on a persistent >20% decline of FEV1 in spirometry. RAS was diagnosed in the presence of a >20% decline of FEV1 concomitant with a >10% decline of the total lung capacity and confirmed by CT scans. Results In this cohort, 115 patients did not develop CLAD at the end of follow up (control group). BOS was observed in 18 patients, whereas RAS was observed in 5 patients. In the BOS group, 7 patients were graded 1, 1 patient was graded 2, and 10 patients were graded 3. There was no significant difference in the percentage of CD8 T cells amongst lymphocytes between the control and the CLAD group (5.2±8.2% vs. 5.7±7.1%, respectively: p=0.40), three weeks after transplantation. In addition, there was also no significant difference between the control and the BOS subgroup (5.2±8.2% vs. 3.9±5.8%, respectively: p=0.27). However, a significant difference was detected between the BOS and RAS groups (3.9±5.8 vs. 12.0±8.6%, respectively: p Conclusion The development of the most severe and frequently early subtype of chronic lung rejection, the restrictive allograft syndrome, is preceeded by a high frequency of cytotoxic effector CD8+ T cells in peripheral blood as early as three weeks post transplantation. Cytotoxic T cells are also known to contribute to acute rejections and might be targeted by multiple immunosuppressive treatments.